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Vector Biology Diagnostics and Public Health Pesticide Development through the Product Development Partnership Route. Janet Hemingway Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK Email [email protected] Public Health Pesticides play a key role in the control of many insect vector borne diseases. These include diseases causing severe human morbidity and mortality, such as malaria, dengue, filariasis, Japanese encephalitis and West Nile. The largest volume of insecticide is used to contain malaria, which still afflicts much of the tropical and sub-tropical world. Malaria elimination was attempted in the 1960s on the back of the discovery and deployment of DDT to control the mosquito vectors and chloroquine to control the parasite infections. Failure of the campaign has often been linked to the appearance of DDT resistance in many of the mosquito vectors, although the lack of political will to maintain the funding, infrastructure and vertical programmes needed for a sustained elimination campaign were probably more relevant. While the campaign failed to achieve its major objectives, the many successes in this early elimination campaign served to underline the make or break role that vector control has both in elimination and sustained control campaigns in areas of high and moderate malaria transmission. It is the lead intervention in the current Global Malaria Action Plan and the only tool that is capable of bringing intense or moderate transmission down to the low levels where elimination supported by drug treatment and vaccination is within reach. However, insecticides, like drugs and antibiotics have a finite product lifespan. The average lifespan of an agrochemical insecticide is approximately 40 years. The longevity of the product is heavily influenced by its efficacy compared to competitor products, the ability of the manufacturer to maintain its licenses to sell in an increasingly complex regulatory environment, and the rate at which the target insects against which it is used become operationally resistant. The market operates well where the market size and net profitability of the product, over the time period over which patent rights reduce generic © 2009 American Chemical Society Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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4 competition, are sufficient to generate a substantive return once the capital costs associated with insecticide production plant, development, manufacture and sales costs have been factored into the calculations. Market size and profit margins within the high volume, low margin, tender-based public health pesticide market for malaria and most other vector borne diseases are not sufficiently large to stimulate industry to develop and maintain a robust pipeline of new Public Health Insecticides. All previous Public Health Pesticides were developed as formulations of existing agrochemical insecticides. While this generated four classes of public health insecticides for operational vector control over four decades trends of increasing selectivity and the move away from contact toxicity to delivery systemically through the crop plant, have meant that newer classes of agrochemicals cannot easily be repurposed for public health use. It is not surprising therefore, that DDT, despite its obvious environmental issues has still been retained for malaria control because of the severely restricted range of available alternatives. Over 20 publicly or charitably funded Product Development Partnerships (PDPs) now exist to share the risk and cost of developing a large range of drugs, vaccines and diagnostics for ‘orphan’ diseases whose market size and value would not warrant individual company investment. These have rejuvenated the R & D activities of the pharmaceutical industry for a range of diseases. The issues around Public Health Pesticides are very similar to those for ‘orphan’ drugs, with the baseline costs of ~US$200Million per new insecticide developed being prohibitive for the agrochemical industry alone to underwrite using normal industrial risk assessments and NPV calculations. The net result of this has been the long term disengagement of the agrochemical industry from development of new compounds into the public health market with a concomitant deskilling of industry in this area. The Innovative Vector Control Consortium (IVCC) is the first PDP established to work with the agrochemical industry to redress this imbalance, by providing access to funding and expertise to stimulate the industry to re-engage 1. Indoor residual spraying (IRS) was developed to routinely bring DDT into contact with the adult female mosquitoes at the most epidemiologically significant point of contact between man and insect. Insecticide impregnated bednets (ITNs) followed in the 1980s, breaking man-mosquito contact for night biting insects and providing both community and personal protection for the users. Long-lasting ITNs (LLINs) were developed in the 1990s using technology to ensure that the insecticide remained on the net for the useful life of the net itself. There has been little innovation in effective treatments since then, despite the seriousness of the health problem. Coils, impregnated mats for emanators and aerosols are readily available in the consumer markets, but there is little direct evidence for these impacting on disease transmission and the annual cost of routinely using these interventions is high despite the low cost of the individual coils or sprays. Establishing whether Public Health Pesticides, presented in different formats to control the vector population, can effectively control disease is nontrivial, as is monitoring the effectiveness of current control campaigns. Data on parasite infection rates in humans and insects, insect population density, insecticide coverage rates, effectiveness of treatment, climate and geography

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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5 need to be efficiently collected and analysed to make the link between disease in man, parasite transmission and interventions affecting the mosquito’s biology and ecology. This data has usually to be collected from very remote areas in very resource poor settings. The Innovative Vector Control Consortium (IVCC) was established in November 2005 with an initial US$50.7M investment from the Bill and Melinda Gates Foundation, to start and address a number of these issues. The initial investment leveraged further funding from the Wellcome Trust (UK), National Institutes of Health, USA and European Union to expand the scope of some of the original diagnostics work. The IVCC was instigated with two separate arms. The first developing better diagnostics and software systems to allow control programmes to monitor and evaluate their vector control interventions, both programmatically and experimentally. The second arm works collaboratively with the agrochemical industry, to develop better formulations of existing insecticides and discovering and developing new insecticide molecules for the public health market. Diagnostics The number of skilled field entomologists able to accurately monitor and evaluate changes in insect vector populations has declined substantially over the last 40 years. The availability of trained staff and the lack of funding to employ such staff within the National Malaria Control Programmes (NMCPs) of Disease Endemic Countries mean that we need to re-align the old labour intensive entomological methods, using modern technology to develop cheap effective high throughput systems that are less labour intensive. These diagnostics also need to be able to rapidly feed information back into the NMCPs in a format that facilitates decision making. The IVCC is developing high throughput DNAbased diagnostics that can be used on dead mosquito collections, passively collected in fixed window traps by householders, to monitor mosquito population densities, their species, insecticide resistance status and malaria sporozoite infection rates (see Figure 1). Development of these simple diagnostics has been massively facilitated by the availability of the Anopheles gambiae genome sequence. The programme has required painstaking use of state of the art molecular techniques, genomics, SNP mapping, QTL and Association mapping coupled to metabolism studies to identify the genes responsible for the insecticide resistance phenotype in the mosquitoes. Linking these resistance genes to SNP markers means that they can then be tracked using simple PCR reactions in the field. SNP markers for infection status, species identification and most of the pyrethroid resistance genes are now available for the major African malaria vector Anopheles gambiae 2-4, and a programme to develop similar markers is underway for An. funestus 5-7. In the same resource poor settings there are also several requirements to monitor the efficacy, effectiveness and longevity of insecticide residues either on bednets or on wall treatments. Undertaking this by HPLC or other laboratory based methodologies is often beyond the resources of the Disease Endemic

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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Figure 1. The collection and analysis of mosquito samples for insecticide resistance, infection status and species using passive collection methods and DNA based diagnostics. Countries. The IVCC has therefore developed simple colorimetric based diagnostics assays that can be used rapidly, cheaply and safely in the field to establish whether treatments contain the biologically relevant level of insecticide to provide protection. Software Systems Although insecticide-based control of adult mosquitoes within the home has been central to malaria and dengue control for over 50 years, current tools to monitor the effectiveness of these interventions are poor. The IVCC, building on the pioneering work on malaria control monitoring and evaluation in southern Africa started by the late Dr Brian Sharp in Durban, South Africa8,9, has developed operational scale software systems for monitoring the impact of interventions. The modular relational database system can be used by programmes to bring together a diversity of disease, operational treatment,

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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7 entomological, spatial and geographical information to aid decisions on which interventions to implement and monitor their effectiveness once initiated. A similar dengue decision support system that can be implemented by municipalities responsible for responding to dengue outbreaks should revolutionise our ability to detect and appropriately respond to this rapidly spreading insect borne disease. The malaria and dengue decision support systems, built of the same basic platform and operable in web and stand alone computer formats, will also allow us to rapidly assess new pesticide-based interventions, at scale, not only for their ability to kill insect and reduce insect population numbers, but also to define the impact of these new interventions, alone or in combination, on disease transmission. While the underlying databases handling this information are complex (see Figure 2) the user interface is designed for deployment in disease endemic countries with data been easily downloaded and user interface screens largely driven by simple drop down menus. These systems are currently being evaluated at operational scale for malaria in southern Africa and by local municipalities for dengue in Mexico.

Figure 2. The modular database structure for collection of data needed for effective monitoring and evaluation of malaria control programmes.

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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New Public Health Pesticides and Formulations Working with industry the IVCC aims to transform the vector control public health pesticide intervention landscape. To date there are only two well validated vector control systems that impact on disease transmission, the use of Long Lasting Insecticide Treated bednets (LLINs) and indoor residual spraying of insecticide (IRS). Larvicides in some urban settings may be cost effective but this intervention is not practical for deployment in rural settings where much of the disease transmission occurs. DDT has been maintained for malaria control as, to date, it is the only insecticide IRS formulation that provides protection on all indoor surfaces for an entire transmission season (>6months) in hyperendemic countries after a single treatment. The IVCC has stimulated the development of new formulations of pyrethroids and organophosphates that should extend the lifespan of these treatments. We hope to see the launch of the first of these new products by the end of 2010. Development of new active ingredients is a much longer and more expensive process. Projects entering the IVCC pipeline are taking one of two approaches; Molecular design against known insecticide target sites within the insect or high throughput screening of chemical libraries. A range of initial lead compounds will be defined over the next 18 months from these initial activities, which can then be refined. The goal is to develop three new insecticides with different modes of action over the next decade. Consumer Products Neither LLINs or IRS are ideal, both are costly to implement and neither are well received by many disease endemic country populations. The IVCC aims both to dramatically improve these interventions and to stimulate industry to bring new interventions to the market. We know that there is a large consumer market for coils, aerosols and insecticide impregnated mats, although these interventions in their current format are not cost effective and have no proven impact on disease transmission, being deployed by the consumers largely to reduce mosquito biting nuisance. Acting as in interface between the consumers, pesticide industry and other industrial and academic players the IVCC is already stimulating the development of novel insecticide-based interventions within the home and testing the efficacy of these interventions in reducing disease transmission. Conclusions Public Health Pesticides are an essential element of insect vector borne disease control programmes. PDPs have a major role in ensuring the stability of public health pesticide supply, engaging with industry to share the risk and plug expertise gaps to ensure that a robust pipeline of new insecticides is developed to replace older chemistries. New diagnostics that allow control programmes to

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

9 monitor the effectiveness of their pesticide based interventions, and ensure that they are able to rapidly detect and respond to adverse changes in the insect vector population that are likely to result in increased disease transmission should ensure that the increased levels of international funds available for malaria and other vector borne disease control are used efficiently and effectively.

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References 1. Hemingway J, Beaty BJ, Rowland M, Scott TW, Sharp BL. The Innovative Vector Control Consortium: improved control of mosquito-borne diseases. Trends in Parasitology 2006;22(7):308-312. 2. Cohuet A, Krishnakumar S, Simard F, et al. SNP discovery and molecular evolution in Anopheles gambiae, with special emphasis on innate immune system. BMC Genomics 2008;19(9):227. 3. Bass C, Williamson MS, Wilding C, Donnelly MJ, Field LM. Identification of the main malaria vectors in the Anopheles gambiae species complex using a TaqMan real-time PCR assay. Malar J. 2007;6:155. 4. Kulkarni MA, Rowland M, Alifrangis M, et al. Occurrence of the leucine-tophenylalanine knockdown resistance (kdr) mutation in Anopheles arabiensis populations in Tanzania, detected by a simplified highthroughput SSOP-ELISA method. Malar J. 2006;5(56). 5. Wondji CS, Hemingway J, Ranson H. Identification and analysis of single nucleotide polymorphisms (SNPs) in the mosquito Anopheles funestus, malaria vector. BMC Genomics 2007;8:5. 6. Wondji CS, Hunt RH, Pignatelli P, et al. An integrated genetic and physical map for the malaria vector Anopheles funestus. Genetics 2005;171(4):177987. 7. Wondji CS, Morgan J, Coetzee M, et al. Mapping a Quantitative Trait Locus (QTL) conferring pyrethroid resistance in the African malaria vector Anopheles funestus. BMC Genomics 2007;8:34. 8. Feachem R, Sabot O. A new global malaria eradication strategy. The Lancet 2008;371(9624):1633-1635. 9. Kelly-Hope L, Ranson H, Hemingway J. Lessons from the past: managing insecticide resistance in malaria control and eradication programmes. The Lancet Infectious Diseases 2008;8(6):387-389.

Clark et al.; Advances in Human Vector Control ACS Symposium Series; American Chemical Society: Washington, DC, 2009.